In "landscape" phage, as in traditional phage-display constructs, foreign peptides or proteins are fused to coat proteins on the surface of the virus particle. Unlike conventional constructs, however, they display thousands of copies of the peptide in a repeating pattern, subtending a major fraction of the viral surface. The phage body serves as an interacting scaffold to constrain the peptide into a particular conformation, creating a defined organic surface structure ("landscape") that varies from one phage clone to the next. A landscape library is a huge population of such phage, encompassing billions of clones with different surface structures and biophysical properties a rich source of new materials for biomedical and other applications. Unlike traditional synthetic materials (polymers, drugs, etc.), these are synthesized "randomly" with no particular application in mind. Users with specific goals must select clones with the desired properties. The specific goal of this project is to select phage that act as artificial antibodies specific for a panel of test antigens. Selection will start with "mosaic" landscape libraries in which each phage is coated with two different random peptides, so they can interact with each other to form complex antigen-binding sites. These libraries are created microbiologically, by co-infecting host cells with separate "parent" libraries; in this way, up to 1,012 different peptide combinations can easily be made in a 1-liter culture. The libraries will be passed over a solid support coated with antigen; unbound phage (the vast majority) will be washed away, and those few phage that remain will be bound to antigen eluted and propagated for the next round of selection. Subsequent rounds of selection will be accomplished by a novel "combinatorial" strategy that allows new combinations of surface peptides combinations that were not present in the initial mosaic library to be tried out. This may compensate partially for the fact that even 1,012 mosaic clones is not enough to represent all possible combinations of peptides from two 109-clone parent libraries. After several rounds of selection, individual mosaic phage clones will be tested quantitatively for their ability to bind antigen. By testing mosaic libraries in this way, with a panel of representative high and low molecular-weight antigens, we will assess the promise of landscape phage as a new type of in vitro immune system.